The activating transcription factor (ATF)/cyclic adenosine monophosphate responsive element-binding (CREB) family consists of transcription factors that bind the cyclic adenosine monophosphate (cAMP) response element (CRE) through highly related, carboxy-terminal basic leucine-zipper (bZip) dimerization domains (Hai et al. (2001) Gene 273, 1-11). Several cDNA clones encoding proteins that can bind to the ATF/CRE site have been isolated. All these cDNAs encode proteins with the bZip DNA binding domain, and the proteins can be grouped into subgroups on the basis of their amino acid similarity. Proteins within each subgroup share significant similarity both inside and outside the bZip domain. Proteins between the subgroups, however, do not share much similarity other than the bZip “motif.” The ATF4 subgroup includes ATF4 (also known as CREB2, TAXREB67, mATF4, C/ATF, or mTR67) (Chevray et al. (1992) Proc. Natl. Acad. Sci. USA 89:5789-93; Hai et al. (1989) Genes Dev. 3:2083-90; Karpinski et al. (1992) Proc. Natl. Acad. Sci. 89:4820-4; Mielnicki et al. (1991) Nucleic Acids Res. 19:6332; Tsujimoto et al. (1991) J. Virol. 65:1420-6; Vallejo et al. (1993) Proc. Natl. Acad. Sci. USA 90:4679-83) and ATFx (also known as ATF5) (Hai et al. (2001) Gene 273:1-11; and Persengiev (2002) Genes Dev. 16:1806-14).
ATF4 is a 381 amino acid protein containing 3 acidic regions, a hallmark of transactivation domains. Its mRNA is ubiquitously expressed and the protein exhibits a short half-life controlled through ubiquitination. ATF4 can form homodimers, but can also heterodimerize with a variety of partners, including transcription factors and kinases. It interacts with transcriptional coactivators and components of the basal transcriptional machinery. Although ATF4-dependent transcriptional repression has been reported, it is thought that the repressive activity was an experimental artifact, and it is generally assumed that ATF4 acts as a transcriptional activator. Disruption of ATF4 activity has been shown to cause severe microphthalmia, anemia, runting, and reduced bone mass in mice.